The candidate's long-term career goal is to become an independent investigator with interdisciplinary expertise in statistical genetics, bioinformatic, and cost-effectiveness analysis to advance individualized colorectal cancer (CRC) prevention in the context of precision medicine. Current guidelines endorse the initiation of screening colonoscopy at age 50 with a 10-year colonoscopy-screening interval for the average-risk population. Although lifestyle, a family history of CRC, and genetic susceptibility influence risk f developing CRC, those factors are not currently incorporated in colonoscopy-screening recommendations. Building on her prior work in colonoscopy screening, the candidate seeks to fill this knowledge gap by optimizing colonoscopy screening according to an individual's lifestyle, family history, and genetic susceptibility. Specifically, the candidate proposes to: 1) develop and validate a risk prediction model for CRC incidence based on lifestyle, family history, and known genetic susceptibility loci; 2) determine optimal age of initiation and interval of colonoscopy screening for individuals characterized as high-risk according to this prediction model; 3) evaluate the cost- effectiveness of a colonoscopy-screening program tailored according to individual's risk; and 4) identify biological pathways and networks that underlie CRCs that arise despite a negative colonoscopy within 5 years (interval CRCs). To achieve these goals, the candidate and her mentors have designed a career development plan for research and educational training to obtain: 1) advanced didactic training in statistical genetics, bioinformatis, and cost-effectiveness analysis; 2) practical experience to synthesize data from multiple sources including epidemiological, bioinformatics, and economic data; 3) enhanced understanding of CRC etiology and genomics; and 4) extensive analytical skills using pooled data from large consortia. To achieve the proposed research aims, the candidate will utilize two large prospective cohort studies, the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), in which data on endoscopy- screening status have biennially collected among 88,902 participants over the last 26 years. Within these cohorts, a substantial number of participants have been characterized for genetic susceptibility to CRC and cases of CRC have been molecularly profiled. The candidate will also validate findings within the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which includes a large independent cohort of men and women. The interdisciplinary mentorship and advisory team comprised of national leaders in epidemiology, statistical genetics, bioinformatics, and decision science will provide the requisite expertise to ensure the success of this proposal and the candidate in her critical transition towards an independent investigator. This integrated examination of lifestyle factors, family history, genetic variation, and the molecular interdependency network of interval CRC may lead to the development of more efficacious and cost-effective CRC screening guidelines that can substantially reduce the U.S.'s overall burden of CRC.